Chain-extended or crosslinked polyethylene oxide/polypropylene oxide/polyethylene oxide block polymer with optional polyester blocks

ABSTRACT

A composition exhibiting reverse thermal gellation properties comprises a block polymer having the structure: 
     
       
         {[A n (BCB)A n ]} m   
       
     
     wherein A is a polyester unit, B is a poly(ethylene oxide) unit, C is a poly(propylene oxide unit, E is a chain extender or crosslinking agent unit, n ranges from 0 to 20, and m is greater than 2, said block polymer possessing an EO (ethylene xide):PO (propylene oxide) ratio ranging from about 0.2:1 to about 40:1, said composition having a final viscosity at a final temperature of more than twice the initial viscosity at an initial temperature, said final temperature being at least 10° C. higher than said initial temperature.

RELATED APPLICATIONS

This application claims priority from U.S. provisional application No.60/138,132, filed Jun. 8, 1999.

FIELD OF THE INVENTION

The present invention relates to novel polymeric compositions based uponA_(n)(BCB)A_(n) polyester/polyether multi-blocks. Compositions accordingto the present invention exhibit unexpectedly exceptional reversethermal gellation (RTG) properties and in preferred embodiments,relatively low viscosities at approximately room temperature or belowand extremely high viscosities at temperatures above room temperature(preferably, at approximately body temperature, i.e., within atemperature range of about 32-40° C., depending upon the species ofanimal to be treated). Compositions according to the present inventionmay be used advantageously in applications which make use of theirreverse thermal gellation properties. Preferred applications for use ofthe present compositions include, for example, medical applicationswhich make advantageous use of the inherent composition characteristicof being of relatively low viscosity at room temperature or below andmuch higher viscosity at elevated temperatures, especially bodytemperature. Compositions according to the present invention may benon-biodegradable or biodegradable, depending upon the application inwhich the composition is to be used.

The present compositions are preferably advantageously used, forexample, in the reduction or prevention of adhesion formation subsequentto medical procedures such as surgery and as lubricants and sealants. Inaddition, compositions according to the present invention may be used ascoatings and transient barriers in the body, for materials which controlthe release of bioactive agents in the body (drug deliveryapplications), for wound and bum dressings and for producingbiodegradable and non-biodegradable articles, among numerous others. Inaddition, compositions according to the present invention mayincorporate cells for delivery to sites within the body (cell-containingcompositions) and allow for their growth and proliferation or for tissueengineering applications. Compositions according to the presentinvention may also be used for treating periodontal disease and ingeneral dental applications, including the intragingival delivery ofbioactive compounds for the treatment of caries or to reduce plaque.

BACKGROUND OF THE INVENTION

There is a wide variety of polymers which are foreign to the human bodyand which are used in direct contact with its organs, tissues andfluids. These polymers are known as polymeric biomaterials. There is acontinuous search for new, improved polymers to provide enhancedmaterials which are biocompatible, have good bioabsorbtive/biodegrableproperties, appropriate mechanical and physical properties and relatedstructural characteristics which find use in the prescribedapplications. Materials which provide superior characteristics as wellas flexibility in formulation, manufacture and delivery of the materialto a situs in the body are especially desirable.

The term “intelligent polymer” refers to a polymeric system able todevelop a “dialog” with its environment, as a result of which itdisplays large and sharp chemical or physical changes, in response tosmall chemical or physical stimuli. These polymers are denominatedsmart, stimuli-responsive or environmentally sensitive polymers.Temperature, pH, ionic strength and electric field are among the mostimportant stimuli, causing phase or shape changes which dramaticallyaffects the optical, mechanical or transport properties of thecompositions. A number of molecular mechanisms exist which can causethese sharp transitions and water plays a crucial role in most of them.These include: ionization, ion exchange, release or formation ofhydrophobically bound water and helix-coil transition.

The desire to find improved polymeric compositions which can be used forspecific medical and dental applications is ever present. A majorproblem which exists in utilizing known polymeric compositions in adiversity of applications, including medical and dental applications isthe ability to deliver polymers to sites within the patient's body ormouth having sufficient viscosities to provide the appropriatephysical/mechanical properties consistent with the task to be performed.This an acute problem especially where high viscosity is requiredbecause the delivery of the polymeric materials is generally verydifficult and their conformability extremely limited.

One approach to solving this problem is that of Hubbell, et al. asdescribed in U.S. Pat. No. 5,410,016. In this reference, the use ofpolymerizable water soluble macromers containing photopolymerizableend-cap groups such as acrylate groups, is described. In the method ofHubbell, in order to provide high viscosity polymeric materials at asite within a patient's body, Hubbell suggests delivering a lowerviscosity mixture of the above-described macromers and thenphotopolymerizing the macromers in situ within the patient's body toobtain high viscosity gels. This approach suffers from the requirementof having to photopolymerize the macromers after they are placed in thebody. Inasmuch as consistency, uniformability, (or homogeneity andreproducibility) of UV polymerization is often difficult to achieve evenin a factory setting, the difficulties of providing consistent UVpolymerization on a case-by-case basis is one major disadvantage of thesystem. In addition, providing conditions to facilitatephotopolymerization in a patient's body is costly, requiring significantexpenditures for photopolymerization equipment as well as high costs forcalibrating and servicing the equipment. Moreover, using an intense UVenergy source at the site of polymerization is difficult and oftendangerous to the patient. The use of prepolymerized polymers representsa clear advantage over the Hubbell process.

One of the most important stimuli for influencing polymeric biomaterialsis temperature. There are numerous biomedical applications where a sharpincrease in viscosity within a narrow and clinically relevanttemperature interval is a crucial feature. The phase transitiontemperature for these polymers is called the Lower Critical SolutionTemperature (LCST). Since the transition is endothermic, the process isdriven by the entropy gain, resulting from the release of watermolecules bound to the hydrophobic groups in the polymer backbone. Afeature common to the polymers exhibiting this behavior is the balancebetween hydrophilic and hydrophobic moieties in the molecules.

The development of temperature-responsive polymers has attracted muchattention in recent years, due to their large clinical potential. Theability to inject, deliver or apply a low viscosity liquid which, uponcontact with the tissue dramatically increases its viscosity is anextremely attractive characteristic. Recently, a number of polymericsystem have been studied, with much of the work focusing onpoly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide)triblocks, because of their clinical potential. Despite their potential,these materials have failed to be used in the clinic because of inherentperformance limitations. A critical inadequacy of these materials isthat their viscosity at physiological temperatures is insufficient toprovide adequate structure for useful biological activity. Insufficientviscosity affects the cohesiveness and mechanical properties of thematerial, which negatively impacts their physical stability andsignificantly reduces their residence time at the implantation site orsite of activity. This fundamental limitation affects importantproperties, thus rendering these polymeric systems unsuitable. Inaddition, these materials release bioactive agents too quickly to be ofclinical relevance.

One additional attrribute of many biomaterials is that thebiodegradable/bioabsorbable. Early biodegradable/bioabsorbable polymersfocused on polylactic and/or polyglycolic acid homopolymers orcopolymers which were used primarily in bioabsorbable sutures. Theseearly polymers suffered from the disadvantage that the polymers tendedto be hard or stiff and often brittle with little flexibility. Inaddition, the kinetics of their degradation tended to be slow in certainapplications, necessitating research on polymers with faster degradationprofiles.

A number of other copolymers utilizing lactic acid, glycolic acid,E-caprolactone, poly(orthoesters) and poly(orthocarbonates),poly(esteramides) and related polymers have been synthesized andutilized in medical applications with some measure of success. Thepolymers tend to be limited, however, by disadvantages which appear inone or more of the following characteristics: flexibility, strength,extensibility, hardness/softness, biocompatability, biodegradability,sterilizability, ease of formulation over a wide range of applicationsand tissue reactivity.

Recent investigative attention has centered on the production ofpolymeric compositions comprising polyester triblocks which are derivedfrom blocks of poly(oxy)alkylene and polyhydroxycarboxylic acids. Theseformulations, among others, have exhibited favorable characteristics foruse to reduce and/or prevent adhesion formulation secondary to surgeryand other medical applications.

Despite the advances that the aforementioned polymeric compositionsrepresent in the field of treating adhesions, with the advance of lessinvasive surgical techniques, work continues to find methods andcompositions which are more easily delivered to sites in the body whichhave been surgically repaired using the newer surgical techniques. Inparticular, laparascopic surgical methods are now being used withincreasing frequency. These methods produce favorable surgical resultswhile significantly limiting the opening through which the surgery isperformed. The limited openings result in increased difficulty todeliver anti-adhesion and related polymers, especially those of highviscosity or which are film-like, which may be advantageously used in anumber of applications.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel polymericmaterials exhibiting reverse thermal gellation properties which may beused in a variety of medical, biological, cosmetic, environmental,mechanical and other applications.

It is an additional object of the invention to provide polymericmaterials which may be manufactured and delivered to a site in apatient's body in liquid or low viscosity form at temperatures belowbody temperature (preferably at or below ambient temperature) whichsignificantly increase in viscosity when delivered to a site at elevatedtemperature (above ambient temperature and preferably body temperature).

It is an additional object of the invention to provide compositionswhich may be delivered at room temperature in the form of low viscositypolymeric compositions, but which significantly increase in viscosityafter being exposed to elevated temperatures.

It is yet another object of the invention to provide polymeric materialswhich may be used to substantially prevent adhesions and which may beeffective for delivering bioactive agents, cells and other biologicalmaterial to sites in patient's body.

It is yet an additional object of the invention to provide polymericmaterials which can be produced in a variety of formulations which, whenexposed to elevated temperatures, result in polymeric materials havingacceptable strength and mechanical properties and exhibit reactivity ornon-reactivity with patient tissue depending upon the desiredapplication.

These and/or other objects of the invention may be readily gleaned fromthe detailed description of the present invention including any one ormore of the embodiments which are described hereinbelow.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to novel polymeric compositions based upon{[A_(n)(BCB)A_(n)]E}_(m) repeating units. In the present compositions Ais a polymer preferably comprising aliphatic ester units (polyester), Bis a poly(ethylene oxide) group, C is a poly (propylene oxide) group, Eis a chain extender or crosslinking agent, n is an integer ranging from0 to 50, preferably 1 to 20 (0 to 20 in the case of non-biodegradablematerials), even more preferably 2 to 16 (0 to 16 in the case ofnon-biodegradable materials) and m is the number of times the triblock(where n is 0) or pentablock (where n is 1 or more) and m is the numberof repeating units in the polymer molecule and is an integer equal to orgreater than 2 (within practical limits, up to about 100,000 or more),preferably ranging from about 2 to about 500, more preferably about 3 to100. Thus, where n is 0, the present invention contemplates polymers ofthe structure {(BCB)E}_(m).

In the present invention, A blocks are preferably derived from hydroxyacid units or their cyclic dimers and the like, even more preferablyα-hydroxy acid units or their cyclic dimers and the like, such as arelated ester or lactone. Preferably the A block comprises α-hydroxyacidunits derived from an aliphatic α-hydroxy carboxylic acid or a relatedacid, ester or similar compound such as, for example, lactic acid,lactide, glycolic acid, glycolide, or a related aliphatichydroxycarboxylic acid or ester (lactone) such as, for example,β-propiolactone, ε-caprolactone, δ-glutarolactone, δ-valerolactone,β-butyrolactone, pivalolactone, α,α-diethylpropiolactone, ethylenecarbonate, trimethylene carbonate, γ-butyrolactone, p-dioxanone,1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione,3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters of α-hydroxybutyricacid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproicacid, α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof.

The use of α-hydroxyacids in the present invention is preferred. The Ablock of the pentablocks of the present invention preferably comprises apoly(α-hydroxy-carboxylic acid), for example, poly(glycolic acid),poly(L-lactic acid), poly(D,L-lactic acid) and polycaprolactone, becausethese polymers will degrade and produce monomeric units which may bemetabolized by the patient.

The B block in the pentablock compositions according to the presentinvention is preferably a (poly)ethylene oxide polymer ranging in sizefrom about 10 ethylene oxide units to about 500 ethylene oxide units,more preferably, about 25 to about 150 ethylene oxide units, even morepreferably about 60 to about 125 ethylene oxide units. The molecularweight of the (poly)ethylene oxide B block generally ranges in size fromabout 440 to about 22,000 atomic mass units and will reflect the numberof monomeric units which are contained within the B block.

The C block is a (poly)propylene oxide polymer which ranges in size fromabout 10 monomeric units to about 500 monomeric units, more preferablyabout 20 monomeric units to about 150 monomeric units, even morepreferably about 25 monomeric units to about 100 monomeric units.

{[A_(n)(BCB)A_(n)]E}_(m) multiblock polymers according to the presentinvention are characterized by their reverse thermal gellationproperties, i.e., their ability to be readily delivered to sites withina patient's body at relatively low initial viscosity (preferably at lessthan about 5,000 cps, even more preferably about 1,000 cps units) atabout ambient temperatures or less (i.e., at less than about 30° C.,more preferably at less than about 23-25° C.) and their ability to gelor substantially increase viscosity from the initial viscosity atelevated temperatures of at least about 30° C., more preferably at aboutbody temperature or higher (i.e., at least about 34-38° C.) such thatthe final viscosity in centipoise units of the polymer at elevatedtemperature is at least two times the initial viscosity of the polymer.In preferred aspects according to the present invention, the finalviscosity in centipoise units of the polymer is at least about fourtimes the viscosity, more preferably at least about ten times theinitial viscosity in centipoise units of the delivered polymer. Incertain embodiments, the final viscosity may be more than 100-foldgreater and in other embodiments more than a 1,000-fold greater than theintitial viscosity. In certain preferred aspects according to thepresent invention, the final viscosity may be more than 10⁶-fold greaterthan the initial viscosity. Polymeric compositions according to thepresent invention may also be characterized by their enhancedcohesiveness and mechanical properties, their superior physicalstability and extended residence time at the implantation site andimproved transport characteristics which produces slower, morecontrollable and reproducible release of bioactive agents from thepolymeric matrix. All of these characteristics represent a fundamentalimprovement compared to polymers based upon poly(ethyleneoxide)/poly(propylene oxide)/poly(ethylene oxide) triblocks.

DETAILED DESCRIPTION OF THE INVENTION

The following terms shall be used in describing the present invention:

The term “patient” is used to describe an animal, including a mammal andpreferably, a human, in need of treatment with compositions according tothe present invention.

The term “viscosity” is used to describe an important characteristic ofpolymeric compositions according to the present invention. Viscosity isa property or quality of compositions according to the present inventionwhich relates to the resistance of the composition to flow. For purposesof the present invention, viscosity is measured in centipoise units asdetermined by a Brookfield Programmable Viscometer using the requiredDV-II+spindle at 0.5 rpm. Compositions according to the presentinvention which have lower viscosities, i.e., viscosities which are lessthan about 1,000 centipoise (cps) units tend to be flowable. As theviscosity of the compostions decreases, the flowability of thecomposition increases. Compositions according to the present inventionwhich have viscosities which are less than about 10,000 cps generallyare flowable and deliverable to most sites within a patient's body.Compositions which have viscosities which are less than about 1,000 cpsare readily flowable and deliverable in nature, whereas thosecompositions which have viscosities which are greater than about 1,000cps tend to be less flowable and less deliverable. It is noted thatcompositions which have viscosities as high as 700,000 cps or more aredeliverable through a syringe with an 18G needle and here, we arereferring to flow and deliverability per se, i.e., not under pressure.

The term “initial viscosity” is used to describe the viscosity ofpolymeric compositions which are delivered at an “initial temperature”,preferably at ambient temperatures or below (i.e., at a temperature ofabout 20-25° C. or less) to sites within a patient's body. The term“final viscosity” is used to describe compositions which have beendelivered to a site in the patient's body or other site and have beenexposed to a “final temperature”, i.e., a temperature which is elevatedor higher (generally, at least about 10° C. higher) than the initialtemperature. Initial viscosities and final viscosities as used in thepresent invention are taken after a composition has been subjected to aninitial temperature or a final temperature, respectively, for a periodsufficient to establish a constant viscosity reading. As a general rule,depending upon the size of the polymeric sample to be tested,establishing a constant viscosity will usually occur on a consistentbasis after approximately 30 minutes or more at constant temperature.

Although the initial temperature and final temperature may vary broadlyover a wide range from a temperature approaching O° C. to temperaturesof 100° C. or more, preferably the initial temperature is approximatelyambient temperature and the final temperature is at least about 10° C.higher than ambient temperature. More preferably, the initialtemperature is no greater than about 30° C., and in the most preferredcase, approximately room temperature (20-25° C.). The final temperatureis at least about 10° C. above the initial temperature, and may beconsiderably above the body temperature of the patient). In preferredembodiments according to the present invention which relate to the useof the present compositions in medical applications, the initialtemperature is generally no greater than about room temperature (i.e.,about 20-23° C.) and the final temperature is approximatelyphysiological temperature (depending upon the animal to be treated, suchtemperatures ranging from about 32-40° C.).

The initial viscosities of compositions of the present invention fallwithin a range which allows delivery of the polymeric composition to asite to be treated or to where the polymeric composition is to be used.Initial viscosities which are consistent with the delivery of thepresent compositions to sites within the patient's body may range fromabout 100 cps to about 10,000 cps or even higher (e.g. 20,000-30,000),preferably about 250 cps to about 5000 cps, more preferably about 250cps to about 2000 cps. Obviously, the lower the viscosity, the morereadily deliverable is the polymer. This characteristic of“deliverability” at the initial viscosity must be weighed against thefinal viscosity of the polymeric composition, in order to obtain anappropriate balance. Also, other considerations, including the geometryof the site will play a role in determining the level of the initialviscosity.

Final viscosities of compositions according to the present inventiongenerally range from about 2500 cps to well over 20,000,000 cps, withpreferred viscosities depending upon the purpose for which a polymer isto be used. Preferred compositions generally will have viscosities whichare higher in order to maximize the inteded effect of the polymer. Inthe case of treating adhesions or providing structural devices in thepatient's body such as barriers, cellular supports and the like, ahigher final viscosity may be preferred in order to obtain the desiredmechanical properties. In the case of delivering bioactive agents orbiological material including cells, the final viscosity used may beless than in other instances.

For purposes of defining the present invention, initial viscosities andfinal viscosities are determined on a Brookfield Programmable Viscometerusing the DV-II+spindle at 0.5 rpm after allowing the composition to setfor a period of at least 30 minutes. Noted here is the fact thatviscosities of certain compositions according to the present inventionmay be so large (substantially in excess of 100,000 cps and in certaincases more than 20,000,000 cps) that measurement is inexact andviscosities are simply estimated.

The term “polymer” is used to describe high molecular weightcompositions according to the present invention which comprise two ormore chain-extended BCB triblocks and are based upon{[A_(n)(BCB)A_(n)]E}_(m) multiblocks as previously defined. Polymersaccording to the present invention may range in molecular weight(average molecular weight) from several hundred to several million ormore and as described, may include oligomers of relatively low molecularweight. Preferred compositions according to the present invention havemolecular weights ranging from about 10,000 to about 100,000, morepreferably about 15,000 to about 60,000.

The terms “poly(ethlyene glycol)”, “PEG”, poly(ethylene oxide), “PEO”and “EO” are used interchangably to describe the present invention.These polymers, of varying weights, are used in the B block of{[A_(n)(BCB)A_(n)]E}_(m) multiblocks, where m is the number of repeatingunits in the polymer molecule. Poly(ethylene oxide) oligomers may alsobe used in chain extenders and crosslinking agents according to thepresent invention.

The terms “poly(propylene glycol)”, “PPG”, poly(propylene oxide) and“PO” are used interchangably to describe the present invention. Thesepolymers, of varying weights, are used in the C block of{[A_(n)(BCB)A_(n)]E}_(m) multiblocks, where m is the number of repeatingunits in the polymer molecule. Poly(propylene glycol) oligomers may alsobe used in chain extenders and crosslinking agents according to thepresent invention.

The term “polyester” is used to describe polyester A blocks of the{[A_(n)(BCB)A_(n)]E}_(m) multiblocks used in polymeric compositionsaccording to the present invention where A is a polymeric polyester unitwhich may be derived from an aliphatic hydroxy carboxylic acid or arelated ester, lactone, dimeric ester, carbonate, anhydride, dioxanoneor related monomer and is preferably derived from an aliphatic α-hydroxycarboxylic acid or related ester, such units derived from the following:including, for example, lactic acid, lactide, glycolic acid, glycolide,or a related aliphatic hydroxycarboxylic acid, ester (lactone), dimericacid or related compound such as, for example, β-propiolactone,ε-caprolactone, δ-glutarolactone, δ-valerolactone, β-butyrolactone,pivalolactone, α,α-diethylpropiolactone, ethylene carbonate,trimethylene carbonate, γ-butyrolactone, p-dioxanone,1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione,3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters of α-hydroxybutyricacid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproicacid, α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof. The use of α-hydroxyacids and their correspondingcylic dimeric esters, especially lactide, glycolide and caprolactone inthe present invention, is preferred. It is noted that in using certainof the described monomers according to the present invention, themonomeric units which are produced are not specifically ester groups,but may include such groups as carbonate groups (polycarbonates), aminoacids (which produce polyamides) and related groups which are derivedfrom the above-described monomers or which contain a nucleophilic groupand an electrophilic group and can be polymerized. It will be understoodthat the term polyester shall encompass polymers which are derived fromall of the above monomers, with those which actually produce ester unitsbeing preferred.

The terms “poly(hydroxy carboxylic acid)” or “poly(α-hydroxy carboxylicacid)” are terms used to describe certain polyester A blocks of{[A_(n)(BCB)A_(n)]E})_(m) multiblocks used in polymeric compositionsaccording to the present invention where A is a polymeric polyester unitderived from an aliphatic hydroxy carboxylic acid or a related ester ordimeric ester and is preferably derived from an aliphatic α-hydroxycarboxylic acid or related ester, including a cyclic dimeric ester, suchas, for example, lactic acid, lactide, glycolic acid, glycolide, or arelated aliphatic hydroxycarboxylic acid or ester (lactone) such as, forexample, ε-caprolactone, δ-glutarolactone, δ-valerolactone,γ-butyrolactone and mixtures, thereof, among numerous others as setforth herein. The use of α-hydroxyacids and their corresponding cylicdimeric esters, especially lactide and glycolide in the presentinvention, is preferred.

The term “multiblock” is used to describe polymers according to thepresent invention which comprise a first polyester A block covalentlylinked to a poly(ethylene oxide) B block as described above, which is,in turn, covalently linked to a poly(propylene oxide) C block which is,in turn, linked to a poly(ethylene oxide) B block which is linked againto a polyester A block and is further reacted with a chain-extender orcrosslinking agent to provide an E block.

The term “pentablock” refers to A_(n)(BCB)A_(n) molecules according tothe present invention which have not been chain extended or crosslinkedto produce {[A_(n)(BCB)A_(n)]E}_(m) polymeric compositions. Pentablocksaccording to the present invention may be terminated by hydroxyl oramine moieties (from polyamides including polymeric amino acids), but inpreferred embodiments, are terminated with hydroxyl groups which can bereadily covalently linked to chain extenders, crosslinking agents orother groups which contain electrophilic moieties, to produce the finalpolymers which are used in the present invention.

The term “EO/PO” ratio is used to describe the ratio of ethylene oxideunits to propylene oxide units in a given BCB triblock. It is thisratio, in combination with the extent of polymerization which isimportant in determining the extent of viscosity change which occursfrom an initial temperature of delivery to a final temperataure. It isalso this ratio and the value of m which primarily determines the degreeand extent of reverse thermal gellation properties. The EO/PO ratio ofthe BCB triblocks used in the pentablock polymeric compositionsaccording to the present invention will range generally from about 40:1(40.0) to about 1:5 (0.2), with a preferred ratio falling within therange of about 7.5:1 (7.5) to about 1:1 (1.0), more preferably about 5:1(5.0) to about 1:1 (1.0). In defining the EO/PO ratio, it is the numberof monomeric units of ethylene oxide in a BCB triblock which arecompared to the number of monomeric units of PPG in the triblock whichprovide the EO/PO ratio. It is noted here that in certain instances,where oligomeric ethylene oxide or propylene oxide units are part of themolecules used to chain extend or crosslink a pentablock A_(n)(BCB)A_(n)molecule, the amount of ethylene oxide or propylene oxide may influencethe RTG characteristics of the polymeric composition and may reflect thecontribution from the ethylene oxide or propylene oxide units which maybe found in blocks other than the BCB triblocks.

The term “BCB triblocks” is used to describe triblocks according to thepresent invention which comprise a triblock of poly(ethyleneoxide)/poly(propylene oxide)/poly(ethylene oxide) blocks.

The term “adhesion” is used to describe abnormal attachments betweentissues or organs or between tissues and implants (prosthetic devices)which form after an inflammatory stimulus, most commonly surgery, and inmost instances produce considerable pain and discomfort. When adhesionsaffect normal tissue function, they are considered a complication ofsurgery. These tissue linkages often occur between two surfaces oftissue during the initial phases of post-operative repair or part of thehealing process. Adhesions are fibrous structures that connect tissuesor organs which are not normally joined. Common post-operative adhesionsto which the present invention is directed include, for example,intraperitoneal or intraabdominal adhesions and pelvic adhesions. Theterm adhesion is also used with reference to all types of surgeryincluding, for example, musculoskeletal surgery, abdominal surgery,gynecological surgery, ophthalmic, orthopedic, central nervous systemand cardiovascular repair. Adhesions may produce bowel obstruction orintestinal loops following abdominal surgery, infertility followinggynecological surgery as a result of adhesions forming between pelvicstructures, restricted limb motion (tendon adhesions) followingmusculoskeletal surgery, cardiovascular complications includingprolonging the operative time at subsequent cardiac surgery, an increasein intracranial bleeding, infection and cerebrospinal fluid leakage andpain following many surgeries, especially including spinal surgery whichproduces low back pain, leg pain and sphincter disturbance.

The term “tissue engineering” is used to describe the use of the presentcompositions in applications which relate to biological substitutes torestore, maintain or improve tissue functions. The field of tissueengineering merges the fields of cell biology, engineering, materialsscience and surgery, to fabricate new functional tissue using livingcells and a matrix or scaffolding which can be natural, synthetic orcombinations of both. Matrices, provided from compositions according tothe present invention, are utilized to deliver cells to desired sites inth body, to define the potential space for engineered tissue and toguide the process of tissue development. Direct injection of a cellsuspension without matrices has been utilized in some cases, but it isdifficult to control the placement of transplanted cells. A majority ofmammalian cell types are anchorage dependent and will die if notprovided an adhesion substrate. Compositions according to the presentinvention can be used in tissue engineering applications, in certainapplications, by functioning as an adhesion substrate, anchoring cellsto be transplanted in a patient to allow survival, growth andultimately, grafting and or anchoring of the transplanted cells tonormal cellular tissue.

The term “bioactive agent” is used throughout the specification todescribe biological active agents which may be delivered to a patient toproduce a biological or pharmacological result. Exemplary bioactiveagents which may be delivered pursuant to the to the present inventioninclude, for example, angiogenic factors, growth factors, hormones,anticoagulants, for example heparin and chondroitin sulphate,fibrinolytics such as tPA, plasmin, streptokinase, urokinase andelastase, steroidal and non-steroidal anti-inflammatory agents such ashydrocortisone, dexamethasone, prednisolone, methylprednisolone,promethazine, aspirin, ibuprofen, indomethacin, ketoralac,meclofenamate, tolmetin, calcium channel blockers such as diltiazem,nifedipine, verapamil, antioxidants such as ascorbic acid, carotenes andalpha-tocopherol, allopurinol, trimetazidine, antibiotics, includingnoxythiolin and other antibiotics to prevent infection, prokineticagents to promote bowel motility, agents to prevent collagencrosslinking such as cis-hydroxyproline and D-penicillamine, and agentswhich prevent mast cell degranulation such as disodium chromoglycate,among numerous others.

In addition to the above agents, which generally exhibit favorablepharmacological activity related to promoting wound healing, reducinginfection or otherwise reducing the likelihood that an adhesion willoccur, other bioactive agents may be delivered by the polymers of thepresent invention include, for example, amino acids, peptides, proteins,including enzymes, hormones, growth factors, carbohydrates, antibiotics(treat a specific microbial infection), anti-cancer agents,neurotransmitters, hormones, immunological agents including antibodies,nucleic acids including antisense agents, fertility drugs, psychoactivedrugs and local anesthetics, among numerous additional agents.

The delivery of these agents will depend upon the pharmacologicalactivity of the agent, the site of activity within the body and thephysicochemical characteristics of the agent to be delivered , thetherapeutic index of the agent, among other factors. One of ordinaryskill in the art will be able to readily adjust the physicochemicalcharacteristics of the present polymers and thehydrophobicity/hydrophilicity of the agent to be delivered in order toproduce the intended effect. In this aspect of the invention, bioactiveagents are administered in concentrations or amounts which are effectiveto produce an intended result. It is noted that the chemistry ofpolymeric composition according to the present invention can be modifiedto accommodate a broad range of hydrophilic and hydrophobic bioactiveagents and their delivery to sites in the patient.

The term “biological material” is used throughout the present inventionto describe cells, tissue and other material of a biological naturewhich may be used to treat a patient using the polymeric compositionsaccording to the present invention. Thus, biological material which maybe delivered using the present compositions includes, for example, stemscells, marrow cells, bone cells, hepatocytes, keratinocytes,chondrocytes, osteocytes, endothelial cells, smooth muscle cells,transplants including transplanted organs, tissues and other cellularmaterial.

The term “chain extender” is used throughout the specification todescribe compounds which are used to link BCB triblocks orA_(n)(BCB)A_(n) pentablocks according to the present invention. In orderto increase the molecular weight of the polymer produced, the BCBtriblock or A_(n)(BCB)A_(n) pentablock is chain-extended usingdifunctional compounds such as diisocyanates, dicarboxylic acidcompounds or derivatives of dicarboxylic acids such as diacyl halides.The product which is formed from the reaction of the chain extender withthe BCB triblock or A_(n)(BCB)A_(n) pentablocks according to the presentinvention will depend upon the chemical nature of the nucleophilic (orelectrophilic) moieties on the A_(n)(BCB)A_(n) pentablock and theelectrophilic (or nucleophilic) moieties on the chain extender. Thereaction products can vary widely to produce different moieties, such asurethane groups and ester groups, among numerous others. The product isgenerally represented as a {[A_(n)(BCB)A_(n)]E}_(m) polymer. Preferably,the nucleophilic BCB triblocks or A_(n)(BCB)A_(n) pentablocks arechain-extended with diisocyanate compounds in order to producechain-extended polymers according to the present invention, although thechemical approaches may vary considerably.

The term “crosslinking agent” is used throughout the specification todescribe chain extenders which have at least three functional orreactive groups, so that the triblocks and pentablocks according to thepresent invention may be chain-extended and crosslinked, providing amore dense and rigid three dimensional structure to polymers accordingto the present invention.

RTG polymers according to the present invention may be described by thefollowing formula: $\frac{BCB}{(E) + {2\left( A_{n} \right)}}.$

Where E is a chain extender (or crosslinking agent) and A is abiodegradable component, preferably a biodegradable ester unit of apolyester and the BCB triblock comprises a PEG block, a PPG block andPEG block. In the present invention, n may range from 0 (the polymer isnon-biodegradable) to 16 ester units (the number of A units is 2A_(n) or32). The molar ratio of the BCB unit to chain extender or crosslinkingunit is generally about 1:1. The molecular weight of the BCB triblock incompositions according to the present invention may range from about1,000 to about 25,000 (in Dalton Units) or more, with a preferredmolecular weight of about 4,500 to about 16,000. In BCB triblocksaccording to the present invention, the weight % of PEG ranges fromabout 13% to about 97% by weight, preferably about 40% to about 80% byweight, with the PPG making up the remaining weight of the triblock.

Synthesis of Polymers According to the Present Invention

In producing A_(n)(BCB)A_(n) pentablocks according to the presentinvention, a BCB triblock is a hydroxyacid, cyclic dimer or a relatedmonomer as otherwise described herein to produce a pentamericA_(n)(BCB)A_(n) pentablock. Once the pentamer is formed, it is reactedwith a chain-extender, E, to produce a chain-extended A_(n)(BCB)A_(n)pentablock of structure {[A_(n)(BCB)A_(n)]E}_(m). Alternatively, thepentameric polymer may be reacted with crosslinking agent to produce acrosslinked polymeric system.

A particularly preferred synthesis of the polyester A block according tothe present invention relies on the use of the cyclic ester or lactoneof lactic acid, glycolic acid or caprolactone. The use of lactide,glycolide or caprolactone as the reactant will enhance the production ofA_(n) blocks which have relatively narrow molecular weight distributions(low polydispersity).

In this preferred method, lactide, glycolide or caprolactone (the cycliclactone, rather than the linear hydroxyacid), is used to synthesize theA_(n)(BCB)A_(n) pentablock. Once the pentablock is obtained, it ispreferably reacted with a diisocyanate, preferably hexamethylenediisocyanate to chain-extend the polymer.

The synthesis of the pentablock A_(n)(BCB)A_(n) preferably proceeds byway of a ring-opening mechanism, whereby the ring opening of thelactide, glycolide or caproclactone is initiated by the hydroxyl endgroups of the BCB chain under the influence of a catalyst such asstannous octoate. An A_(n)(BCB)A_(n) type pentablock is generated atthis point, the molecular weight of which is a function of both themolecular weight of the central BCB pluronic block, and the length ofthe polyester, preferably PLA, PGA or PCL lateral block(s). Typically,the molecular weight of the pentablock ranges from about 5,000 to about50,000 (but may be as low as 1,500 or less and as high as 100,000 ormore). After synthesis of the A_(n)(BCB)A_(n) pentablock, the finalpolymer is preferably obtained by chain extending the hydroxylterminated triblocks with difunctional reactants such as isocyanates,most preferably, hexamethylene diisocyanate.

The chemical and physical properties of the different polymers will varyas a function of different parameters, the molecular weight andcomposition of the BCB triblock, the A segments, and most importantly,the value of m of in the {[A_(n)(BCB)A_(n)]E}_(m) polymeric compositionsaccording to the present invention.

Having generally described the invention, reference is now made to thefollowing examples intended to illustrate preferred embodiments andcomparisons but which are not to be construed as limiting to the scopeof this invention as more broadly set forth above and in the appendedclaims.

EXAMPLES

The synthesis of the polymers is presented in the following examples. Ingeneral, where solvent is used, it is dried and distilled prior to use.Nitrogen is used dry at all times. All other materials are dried anddistilled prior to use. Pluronic F-127, is available from Sigma or BASF.

Example 1 Synthesis of [((1)-LA)₂-F 127-((1)-LA)]₂

40 grams Pluronic F-127 (molecular weight 12,600) were dried undervacuum at 90° C. for 1.5 hr. in an Erlenmeyer flask, 1.6 gram(1)-Lactide and 0.18 gram catalyst (stannous 2-ethyl hexanoate) (0.43%)were added to Pluronic F-127. The reaction was carried out in a sealedflask, under a dry nitrogen saturated atmosphere, for two and half hoursat 145° C.

The product is a water soluble white, brittle solid, at roomtemperature. The DSC analysis showed a Tg around −60° C. and a meltingendotherm at 57° C.

Example 2 Synthesis of Poly[(1)-LA)₂-F 127-(1)-LA)₂-HDI]

32.1 grams ((1)-LA)₂-F127-((1)-LA)₂ obtained in Example 1 were dried ina three-necked flask under vacuum at 90° C. for 1.5 hr. 0.42 gramHexamethylene diisocyanate (HDI) and 0.20 gram catalyst (stannous2-ethyl hexanoate) (0.61%) were reacted with ((1)-LA)₂-F127-((1)-LA)₂for 15 minutes, under mechanical stirring (160 rpm) and dry nitrogenatmosphere, at 80° C.

The product is a water soluble white brittle solid, at room temperature.The DSC analysis showed a Tg around −60° C. and a melting endotherm at55° C.

Example 3 Synthesis of ((1)-LA)₄-F127-((1)-LA)₄

40.0 gr. Pluronic F-127 were dried under vacuum at 90° C. for 1.5 hr.And then, 3.14 grams (1)-Lactide and 0.18 gram catalyst (stannous2-ethyl hexanoate ) (0.45%) were added the dry F-127. The reaction wascarried out in a sealed flask, under a dry nitrogen saturatedatmosphere, for two and half hours at 145° C.

The product is a water soluble, brittle solid, at room temperature. TheDSC analysis showed a Tg around −59° C. and a melting endotherm at 51°C.

Example 4 Synthesis of Poly [((1)-LA)₄-F127-((1)-LA)₄-HDI]

35.0 grams of the ((1)-LA)₄-F-127-((1)-(LA)₄ obtained in Example 3 weredried in a three-necked flask under vacuum at 90° C. for 1.5 hr. 0.45gram Hexamethylene diisocyanate (HDI) and 0.11 gram catalyst (stannous2-ethyl hexanoate) (0.31%) were added to ((1)-LA)₄-F 127-((1)-LA)₄, andreacted for 15 minutes, under mechanical stirring (160 rpm) and drynitrogen atmosphere, at 80° C.

The product is a water soluble, brittle solid, at room temperature. TheDSC analysis showed a Tg around −59° C. and a melting endotherm at 49°C.

Example 5 Synthesis of F127-HDI-F127

30.0 gr. of F-127 were dried in a three-necked flask under vacuum at100° C. for 1.5 hr. 0.20 gram Hexamethylene diisocyanate (HDI) and 0.38gram catalyst (stannous 2-ethyl hexanoate) (1.2%) were added to F-127,and reacted with the F-127 for 30 minutes under mechanical stirring (160rpm) and dry nitrogen atmosphere, at 80° C.

The product is a water soluble, brittle solid, at room temperature. TheDSC analysis showed a Tg around −60° C. and a melting endotherm at 56°C.

Example 6 Synthesis of ((1)-LA)₂-F127-HDI-F127-((1)-LA)₂

30.6 grams F127-HDI-F127 obtained in Example 5 were mixed with 0.61 gram(1)-Lactide and 0.346 gram catalyst (stannous 2-ethyl hexanoate). Thereaction was then carried out in a three-necked flask at 150° C., undermechanical stirring (160 rpm) and dry nitrogen atmosphere.

The product is a water soluble, brittle solid, at room temperature. TheDSC analysis showed a Tg around −59° C. and a melting endotherm at 51°C.

Example 7 Synthesis of ((1)-LA)₄-F127-HDI-F127-((1)-LA)₄

30.6 grams F127-HDI-F127 obtained in Example 5 were mixed with 1.23grams (1)-Lactide. 0.346 gram catalyst (stannous 2-ethyl hexanoate) wereadded to F127-HDI-F127, and the reaction was carried out in athree-necked flask at 150° C., under mechanical stirring (160 rpm) anddry nitrogen atmosphere.

The product is a water soluble, brittle solid, at room temperature. TheDSC analysis showed a Tg around −58° C. and a melting endotherm at 56°C.

Example 8 Synthesis of Poly [((1)-LA),-F127-HDI-F127-((1)-LA)₂-HDI]

31.1 grams ((1)-LA)₂-F127-HDI-F127-((1)-LA)₂ obtained in Example 6 weremixed with 0.204 gram Hexamethylene diisocyanate (HDI). Catalyst(stannous 2-ethyl hexanoate) was added at a weight percentage of 0.26%to the reactants.

The reaction was carried out in a three necked flask at 10020 C. undermechanical stirring (160 rpm) and dry nitrogen atmosphere.

The product is a water soluble, brittle solid, at room temperature. TheDSC analysis showed a Tg around −57° C. and a melting endotherm at 55°C.

Example 9 Synthesis of Poly [((1)-LA)₄-F127-HDI-F127-((1)-LA)₄-HDI]

31.1 grams ((1)-LA)₄-F127-HDI-F127-((1)-LA)₄ obtained in Example 7 weremixed with 0.202 gram Hexamethylene diisocyanate (HDI). Catalyst(stannous 2-ethyl hexanoate) was then added at a weight percentage of0.26% to the reactants. The reaction was carried out in a three-neckedflask at 100° C. under mechanical stirring (160 rpm) and dry nitrogenatmosphere.

The product is a water soluble, brittle solid, at room temperature. TheDSC analysis showed a Tg around −59° C. and a melting endotherm at 53°C.

Example 10 Synthesis of Poly [F-127-HDI]

50 grams Pluronic F-127 were dried under vacuum at 90° C. for 1.5 hoursin an Erlenmeyer flask. 0.67 grams Hexamethylene diisocyanate (HDI) and0.160 gram catalyst (stannous 2-ethyl hexanoate) (0.32 wt %) were addedto Pluronic F-127 and reacted for 12 hours minutes under mechanicstirring (160 rpm) and dry nitrogen atmosphere, at 80° C.

The product obtained is a water soluble white solid, at roomtemperature. The DSC analysis showed a Tg of approximately −61° C. and ameltling endotherm at 57° C.

Example 11 Synthesis of Poly [(Cl)-F127-(Cl)]

40 grams of F-127 were dried under vacuum at 100° C. for 3 hours andthen 1.11 gram caprolactone and 0.16 gram catalyst (stannous 2-ethylhexanoate) (0.39%) were added to the dry F-127. The reaction was carriedout in a sealed flask, under dry nitrogen saturated atmosphere, forthree hours at 145° C. The product is a water soluble, brittle, whitesolid, with a melting endotherm of approximately 54° C.

Example 12 Synthesis of Poly [(Cl)-F127-(Cl)]-HDI

20.6 grams of [(Cl)-F127-(Cl)], obtained in Example 11, were dried in athree-necked flask under vacuum at 100° C., for 3 hours. Thereafter,−0.31 gram Hexamethylene Diisocyanate (HDI) and 0.16 gram catalyst(stannous 2-ethyl hexanoate) (0.76%) were reacted with [(Cl)-F127-(Cl)]for 15 minutes, under mechanical stirring and a dry nitrogen atmosphere,at 80° C.

The product is a water soluble, white solid, with a Tg around −61° C.and a melting endotherm at 53° C.

It is to be understood that the examples and embodiments describedhereinabove are for the purposes of providing a description of thepresent invention by way of example and are not to be viewed as limitingthe present invention in any way. Various modifications or changes thatmay be made to that described hereinabove by those of ordinary skill inthe art are also contemplated by the present invention and are to beincluded within the spirit and purview of this application and thefollowing claims.

What is claimed is:
 1. A polymeric composition exhibiting reversethermal gellation properties comprising polymers according to thestructure: {[A_(n)(BCB)A_(n)]}_(m) where A is a polyester unit, B is apoly(ethylene oxide) unit, C is a poly(propylene oxide) unit, E is achain extender unit, n ranges from 0 to 20 and m is greater than 2, saidpolymeric composition having a EO/PO ratio ranging from about 0.2:1 toabout 40:1, said composition having a final viscosity at a finaltemperature which is more than twice the initial viscosity of thecomposition at an initial temperature, said final temperature being atleast 10° C. higher than said initial temperature.
 2. The compositionaccording to claim 1 wherein said polyester unit is derived from thepolymerization of monomers selected from the group consisting of lacticacid, lactide, glycolic acid, glycolide, β-propiolactone,ε-caprolactone, δ-glutarolactone, δ-valerolactone, β-butyrolactone,pivalolactone, α,α-diethylpropiolactone, ethylene carbonate,trimethylene carbonate, γ-butyrolactone, p-dioxanone,1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione,3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters of α-hydroxybutyricacid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproicacid, α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof.
 3. The composition according to claim 1 wherein saidpolyester unit is biodegradable or biocrodible.
 4. The compositionaccording to claim 1 wherein said polyester comprises poly(aliphatichydroxy carboxylic acid).
 5. The composition according to claim 1wherein said polyester comprises poly(aliphatic α-hydroxy carboxylicacid).
 6. The composition according to claim 1 wherein said polyester isobtained from polymerization of a lactone selected from the groupconsisting of lactide, glycolide, caprolactone and mixtures, thereof. 7.The composition according to claim 1 wherein said EO/PO ratio rangesfrom about 7.5:1 to about 1:1 and said BCB block has a molecular weightranging from about 1,000 to about 25,000 dalton units, said compositionhaving a final viscosity at approximately physiological temperaturewhich is more than 10 times the initial viscosity of the composition atambient temperature.
 8. The composition according to claim 1 which isnon-biodegradable.
 9. A polymeric composition exhibiting reverse thermalgellation properties comprising a crosslinked polymeric compositionwhich is formed by reacting a polymer A_(n)(BCB)A_(n) with acrosslinking agent where A is a polyester unit, B is a poly(ethyleneoxide) unit, C is a poly(propylene oxide) unit and n ranges from 0 to20, said polymeric composition comprising at least 3 A_(n)(BCB)A_(n)units, said composition having a EO/PO ratio ranging from about 0.2 toabout 40 and exhibiting a final viscosity at a final temperature whichis more than twice the initial viscosity of the composition at aninitial temperature, said final temperature being at least 10° C. higherthan said initial temperature.
 10. The composition according to claim 9wherein said polyester unit is derived from the polymerization ofmonomers selected from the group consisting of lactic acid, lactide,glycolic acid, glycolide, β-propiolactone, ε-caprolactone,δ-glutarolactone, δ-valerolactone, β-butyrolactone, pivalolactone,α,α-diethylpropiolactone, ethylene carbonate, trimethylene carbonate,γ-butyrolactone, p-dioxanoiie, 1,4-dioxepan-2-one,3-methyl-1,4-dioxane-2,5-dione, 3,3,-dimethyl-1-4-dioxane-2,5-dione,cyclic esters of α-hydroxybutyric acid, α-hydroxyvaleric acid,α-hydroxyisovaleric acid, α-hydroxycaproic acid,α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, Δ-hydroxyhcptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof.
 11. The composition according to claim 9 wherein saidpolyester unit is biodegradable or bioerodible.
 12. The compositionaccording to claim 9 wherein said polyester comprises poly(aliphatichydroxy carboxylic acid).
 13. The composition according to claim 9wherein said polyester comprises poly(aliphatic α-hydroxy carboxylicacid).
 14. The composition according to claim 9 wherein said polyesteris obtained from polymerization of a lactone selected from the groupconsisting of lactide, glycolide, caprolactone and mixtures, thereof.15. The composition according to claim 9 wherein said EO/PO ratio rangesfrom about 7.5:1 to about 1:1 and said BCB block has a molecular weightranging from about 1,000 to about 25,000 dalton units, said compositionhaving a final viscosity at approximately physiological temperaturewhich is more than 10 times the initial viscosity of the composition atambient temperature.
 16. The composition according to claim 9 which isnon-biodegradable.